Mitochondria DNA levels identified as potential biomarker to better manage this common cancer and chemotherapy-induced side effect

Breast cancer patients undergoing chemotherapy often experience severe and persistent tiredness. In a recent study, a team led by researchers from the National University of Singapore (NUS) developed a novel approach to identify the onset of this common side effect and objectively follow its development.

A team led by Associate Professor Alexandre Chan (centre) had developed a novel approach to identify the onset of cancer-related fatigue. With him are two members of the NUS research team, Dr Maung Shwe (left) and Ms Angie Yeo (right).

Currently, cancer-related fatigue is mainly self-reported by patients, and there is no biomarker that could allow clinicians to objectively monitor the severity of fatigue. Findings from the NUS study suggest that measuring the level of genetic material in the blood could help doctors identify patients who are suffering from cancer-related fatigue and develop strategies to better manage this side effect in patients.

“Cancer-related fatigue, which is often poorly managed, increases the severity of distress among patients and adversely affects their quality of life. By uncovering the biomechanisms underlying the condition, we could possibly develop strategies to alleviate the undesirable effect in patients,” said Associate Professor Alexandre Chan, who is from the Department of Pharmacy at the NUS Faculty of Science, and the leader of the research team.

The findings were first published online in the journal Breast Cancer Research and Treatment in early 2018.

Cancer-related fatigue in breast cancer patients

Breast cancer, if treated early, is highly curable. However, survivors of early-stage breast cancer are often afflicted by complications that are associated with the cancer and its treatment.

One of the most prevalent side effects of chemotherapy in breast cancer patients is cancer-related fatigue. Managing this condition is challenging due to a lack of clinical understanding on how it comes about. Furthermore, cancer-related fatigue is subjective in nature, making it difficult for doctors to monitor.

To identify the cause of cancer-related fatigue, the team led by Assoc Prof Chan studied 108 breast cancer patients in Singapore at two time points: before they received chemotherapy treatment, and six weeks after initiation of treatment. At each time point, participants were required to complete a series of questionnaires and undergo assessments. In addition, blood samples were collected from participants and analysed. The study was carried out from November 2014 to July 2017.

The results showed that a significant proportion (43.5 per cent) of the participants experienced worsening fatigue over time. Furthermore, the findings revealed that the participants who developed fatigue had lower levels of mitochondria DNA content in their blood samples than those who did not develop the condition. Mitochondria are “power stations” of cells in the body and they carry their own set of genetic instructions, called mitochondrial DNA (mtDNA), which are responsible for encoding a portion of genes required for mitochondrial function. Failures of the mitochondria – which is associated with abnormal levels of mitochondrial DNA – could lead to a host of disorders, including chronic fatigue.

The team’s analysis also showed that greater reduction of mtDNA content is associated with worsening of physical fatigue. The results demonstrated that every one unit reduction of mtDNA content was associated with a 4 per cent increase in the level of cancer-related fatigue. According to Assoc Prof Chan, a probable explanation could be that physical fatigue, characterised by generalised weakness or lack of energy in the muscles, could arise from disturbances in energy production during mitochondrial dysfunction.

“This is the first study to show that reduction of mtDNA content in blood is associated with the onset of cancer-related fatigue in early-stage breast cancer patients receiving chemotherapy. While we are optimistic that the findings could apply to other forms of cancer, we need to conduct more studies to validate this hypothesis,” explained Assoc Prof Chan.

Better management of cancer-related fatigue

“These exciting findings encourage us to further evaluate the use of mtDNA content as a biomarker to monitor for cancer-related fatigue. The knowledge will also enable us to look at ways to preserve mtDNA content during chemotherapy,” he added.

Assoc Prof Chan and his team will be studying how changes in mtDNA content correspond with patient’s reporting of fatigue in respond to therapeutic interventions. They also plan to evaluate whether certain foods or diets, as well as Traditional Chinese Medicine, supplements and exercise, can help to reduce cancer-related fatigue in patients and survivors of cancer.